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EC number: 204-524-2 | CAS number: 122-14-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 June 1992 - 2 October 1992
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 993
- Report date:
- 1993
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-1 (Chronic Toxicity)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPP 82-7
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Fenitrothion
- EC Number:
- 204-524-2
- EC Name:
- Fenitrothion
- Cas Number:
- 122-14-5
- Molecular formula:
- C9H12NO5PS
- IUPAC Name:
- O,O-dimethyl O-3-methyl-4-nitrophenyl phosphorothioate
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 90617
Purity: 94.3 %
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Standar strain and species
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Canada
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 50-53 days
- Weight at study initiation: 237-289 g (males), 168-215 g (females )
- Fasting period before study: None
- Housing: Individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 15 days
DETAILS OF FOOD AND WATER QUALITY:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: 30 June 1992 - 2 October 1992
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- Dietary incorporation
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- Dietary concentrations were 0, 6, 20, 60 and 200 ppm; corresponding to 0, 0.40, 1.32, 3.99 and 13.8 mg/kg bw/d in males; 0, 0.46, 1.56, 4.85 and 17.6 mg/kg bw/d in females.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily (continuous)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm
- Remarks:
- Control (basal diet)
- Dose / conc.:
- 6 ppm
- Remarks:
- 0.40 and 0.46 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 20 ppm
- Remarks:
- 1.32 and 1.56 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 60 ppm
- Remarks:
- 3.99 and 4.85 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 200 ppm
- Remarks:
- 13.8 and 17.6 mg/kg bw/d in males and females, respectively
- No. of animals per sex per dose:
- 12/sex (main groups)
15/sex (cholinesterase activity assessment) - Control animals:
- yes, concurrent no treatment
- Details on study design:
- Groups of 12 male and 12 female Sprague-Dawley rats for the main study and groups of 15 male and 15 female Sprague-Dawley rats for cholinesterase assessment received fenitrothion, in powdered Certified PMI Rodent Chow at concentrations of 0, 6, 20, 60 and 200 ppm (corresponding to 0, 0.40, 1.32, 3.99 and 13.8 mg/kg bw/d in males; 0, 0.46, 1.56, 4.85 and 17.6 mg/kg bw/day in females) for 13 weeks.
- Positive control:
- Not required
Examinations
- Observations and examinations performed and frequency:
- All animals were observed twice a day for their toxic signs and mortality. Body weight was recorded weekly and days of behavioural testing. Food consumption was recorded weekly for all animals.
Main study animals: Functional observational battery (FOB) and motor activity were tested at prestudy and 4th, 8th and 13th weeks of treatment.
Cholinesterase test animals: Erythrocyte, plasma and brain cholinesterase activities were determined on 5 rats/sex/group at 4, 8 and 13 weeks. - Sacrifice and pathology:
- At the completion of the study, 6 rats/sex/group were randomly selected for perfusion and those in the control and high dose groups underwent a neuropathological evaluation. The remaining animals in each group (6/sex) had their brains removed and then were subjected to necropsy. The brain of each of non-perfused rats in the control and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP).
- Statistics:
- Study parameters were assessd and compared to controls using appropriate statistical analyses.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Four females in the 200 ppm group showed tremors on one or two days during the second week of treatment. The 200 ppm group females also showed a higher incidence of muzzle staining and brown staining along the tail during the study compared to the control group.
- Mortality:
- no mortality observed
- Description (incidence):
- No animals died and none were sacrificed prior to study completion
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Both males and females in the 200 ppm group and females in the 60 ppm group had significantly reduced body weights compared to the control group on Day 7. The 200 ppm group's body weight remained significantly lower on Day 14 and 21 for males and from Days 7 to 42 for females
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption by the 200 ppm group males and females were significantly lower than the control group from Days 0 to 7. Food consumption by the 200 ppm group females remained significantly reduced from Days 7 to 14 but then increased significantly from Days 28 to 56 and from 84 to 91.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Reductions in blood and brain cholinesterase levels were noted for males in the 60 and 200 ppm groups and females in the 20, 60 and 200 ppm groups.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant differences considered to be related to treatment were seen for the qualitative components of the FOB. Significantly lower values for the 200 ppm group females in forelimb grip strength during the 4th week and in hindlimb grip strength during the 8th week occurred. These differences were considered not to be indicative of neurotoxicity taking lower body weights for the 200 ppm group females. Body temperature values as well as motor activity levels were not significantly different between control and fenitrothion-treated groups.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- No gross pathological findings or neuropathological changes (including brain measurements) seen were attributed to treatment with fenitrothion. No significant increases in glial fibrillary acidic protein were detected between the control and high dose groups for either male or females.
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 20 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 60 ppm
- System:
- nervous system
- Organ:
- neurons
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Summary of bodyweights (g)
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Males |
|
|
|
|
|
Day 0 |
264.2 |
262.7 |
265.3 |
266.0 |
263.6 |
Day 7 |
318.4 |
314.7 |
320.6 |
319.6 |
298.4** |
Day 14 |
359.4 |
355.1 |
364.3 |
362.5 |
336.8** |
Day 21 |
388.6 |
384.7 |
395.2 |
394.9 |
372.3* |
Day 26 |
413.1 |
410.9 |
421.6 |
417.7 |
393.1 |
Day 27 |
409.3 |
406.0 |
419.0 |
415.4 |
392.5 |
Day 28 |
414.0 |
409.8 |
423.8 |
421.1 |
401.7 |
Day 35 |
439.1 |
428.7 |
453.3 |
447.8 |
429.5 |
Day 42 |
465.2 |
454.5 |
475.0 |
473.5 |
456.8 |
Day 49 |
488.2 |
472.8 |
496.0 |
494.2 |
479.1 |
Day 54 |
503.2 |
495.3 |
511.1 |
509.7 |
484.4 |
Day 55 |
496.6 |
492.9 |
508.4 |
505.3 |
482.3 |
Day 56 |
502.2 |
488.3 |
512.1 |
506.4 |
497.4 |
Day 63 |
518.8 |
503.1 |
254.2 |
524.5 |
509.1 |
Day 70 |
536.7 |
520.4 |
539.1 |
541.2 |
525.5 |
Day 77 |
553.6 |
538.6 |
553.6 |
558.7 |
539.7 |
Day 84 |
563.4 |
549.3 |
564.8 |
570.6 |
552.3 |
Day 89 |
569.5 |
570.8 |
581.6 |
584.5 |
554.7 |
Day 90 |
563.2 |
564.4 |
573.0 |
579.3 |
551.2 |
Day 91 |
566.8 |
556.0 |
569.7 |
577.7 |
558.8 |
Females |
|
|
|
|
|
Day 0 |
189.2 |
188.9 |
186.8 |
185.6 |
186.5 |
Day 7 |
213.8 |
211.3 |
209.0 |
204.9* |
186.0** |
Day 14 |
226.8 |
226.4 |
225.4 |
219.9 |
190.2** |
Day 21 |
244.1 |
242.7 |
238.1 |
234.7 |
210.6** |
Day 26 |
249.7 |
251.4 |
246.6 |
243.4 |
216.2** |
Day 27 |
251.3 |
250.7 |
247.8 |
242.5 |
215.4** |
Day 28 |
255.9 |
253.2 |
248.1 |
246.5 |
226.4** |
Day 35 |
269.3 |
264.8 |
261.0 |
257.4 |
246.4** |
Day 42 |
280.8 |
276.5 |
270.5 |
268.6 |
216.8* |
Day 49 |
290.8 |
280.4 |
277.0 |
279.6 |
277.1 |
Day 54 |
288.6 |
283.3 |
279.3 |
284.3 |
271.2 |
Day 55 |
287.1 |
280.4 |
277.9 |
282.7 |
268.5 |
Day 56 |
295.8 |
286.1 |
279.1 |
284.9 |
282.2 |
Day 63 |
300.7 |
292.5 |
288.6 |
296.5 |
284.7 |
Day 70 |
307.0 |
300.6 |
291.4 |
304.2 |
291.6 |
Day 77 |
314.0 |
308.0 |
301.5 |
313.0 |
299.8 |
Day 84 |
319.0 |
313.6 |
306.3 |
315.8 |
305.3 |
Day 89 |
319.1 |
313.8 |
306.2 |
317.3 |
305.5 |
Day 90 |
316.5 |
311.0 |
302.9 |
312.3 |
302.8 |
Day 91 |
318.4 |
312.2 |
304.7 |
315.6 |
307.2 |
*significantly different to controls (p<0.05); **p<0.01
Summary of food consumption (g/day)
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Males |
|
|
|
|
|
Day 0 - 7 |
196.5 |
194.7 |
201.6 |
200.9 |
182.2** |
Day 7 - 14 |
203.2 |
197.2 |
208.9 |
207.7 |
194.8 |
Day 14 - 21 |
206.3 |
202.9 |
212.0 |
211.5 |
209.5 |
Day 21 - 28 |
202.2 |
199.0 |
204.5 |
204.8 |
211.2 |
Day 28 - 35 |
204.2 |
199.0 |
210.9 |
204.8 |
211.8 |
Day 35 - 42 |
213.2 |
199.4 |
204.1 |
209.8 |
214.8 |
Day 42 - 49 |
217.0 |
197.9** |
208.5 |
211.9 |
213.3 |
Day 49 - 56 |
208.8 |
197.0 |
205.3 |
206.0 |
213.3 |
Day 56 - 63 |
211.1 |
200.5 |
207.7 |
208.1 |
213.6 |
Day 63 - 70 |
215.3 |
203.1 |
205.5 |
207.0 |
210.1 |
Day 70 - 77 |
215.6 |
205.4 |
206.2 |
211.9 |
210.6 |
Day 77 - 84 |
208.9 |
204.3 |
207.5 |
214.9 |
215.3 |
Day 84 - 91 |
199.6 |
194.7 |
199.3 |
204.0 |
206.7 |
Females |
|
|
|
|
|
Day 0 - 7 |
139.3 |
137.1 |
137.5 |
135.7 |
119.3** |
Day 7 - 14 |
143.3 |
138.8 |
142.3 |
140.4 |
100.9** |
Day 14 - 21 |
151.1 |
149.9 |
145.7 |
148.1 |
145.2 |
Day 21 - 28 |
145.7 |
141.9 |
140.8 |
143.9 |
154.4 |
Day 28 - 35 |
149.6 |
141.0 |
141.9 |
151.2 |
167.4** |
Day 35 - 42 |
152.9 |
145.4 |
141.4 |
150.4 |
173.9** |
Day 42 - 49 |
151.6 |
143.1 |
146.8 |
153.9 |
180.7** |
Day 49 - 56 |
148.2 |
141.6 |
139.1 |
147.5 |
164.8** |
Day 56 - 63 |
150.4 |
147.3 |
145.1 |
159.1 |
165.8 |
Day 63 - 70 |
151.8 |
145.0 |
143.8 |
153.6 |
160.3 |
Day 70 - 77 |
152.0 |
145.9 |
146.2 |
153.0 |
163.2 |
Day 77 - 84 |
149.6 |
146.8 |
145.9 |
150.3 |
161.2 |
Day 84 - 91 |
142.9 |
139.8 |
135.6 |
145.8 |
159.9* |
*significantly different to controls (p<0.05); **p<0.01)
Summary of FOB
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Females |
|
|
|
|
|
Forelimb grip strength (g) |
|
|
|
||
Week 3 |
1120.4 |
1095.0 |
1100.0 |
1084.2 |
998.8** |
Week 7 |
1091.3 |
1111.3 |
1066.7 |
1102.5 |
1036.3 |
Week 12 |
1182.5 |
1157.1 |
1051.3 |
1036.7 |
971.7 |
Hindlimb grip strength (g) |
|
|
|
||
Week 3 |
773.3 |
797.1 |
760.0 |
765.8 |
737.5 |
Week 7 |
766.3 |
792.5 |
755.8 |
726.3 |
658.8** |
Week 12 |
908.3 |
982.1 |
915.0 |
884.6 |
808.8 |
*significantly different to controls (p<0.05); **p<0.01
Summary of cholinesterase activity
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Males |
|
|
|
|
|
Plasma cholinesterase (U/L) |
|
|
|
||
Week 4 |
349.0 |
350.4 |
292.2 |
220.0** |
181.4** |
Week 8 |
379.0 |
299.0 |
295.4 |
196.0* |
155.8** |
Week 13 |
359.5 |
299.8 |
313.0 |
231.2* |
216.6** |
Erythrocyte cholinesterase (U/L) |
|
|
|
||
Week 4 |
2255.0 |
2117.0 |
2131.4 |
1711.0* |
1206.4** |
Week 8 |
2106.0 |
2054.8 |
1839.8 |
1519.4** |
1205.8** |
Week 13 |
2186.5 |
1978.0 |
1978.8 |
1815.0 |
1299.2** |
Brain cholinesterase (U/L) |
|
|
|
||
Week 4 |
10.06 |
10.08 |
9.62 |
8.00** |
3.52** |
Week 8 |
8.30 |
7.60 |
8.66 |
7.19 |
3.49** |
Week 13 |
9.53 |
9.26 |
9.51 |
8.18** |
4.00** |
Females |
|
|
|
|
|
Plasma cholinesterase (U/L) |
|
|
|
||
Week 4 |
1533.0 |
1194.6 |
720.4 |
513.4* |
314.0*** |
Week 8 |
2159.4 |
1914.4 |
938.8** |
505.6** |
324.8** |
Week 13 |
2888.4 |
1396.0 |
976.2 |
661.8** |
376.8*** |
Erythrocyte cholinesterase (U/L) |
|
|
|
||
Week 4 |
2331.6 |
2218.6 |
1880.4* |
1499.6** |
1162.2** |
Week 8 |
1601.0 |
1589.8 |
1332.6 |
1175.8 |
822.5 |
Week 13 |
1650.0 |
1889.8 |
1668.2 |
1217.6 |
1021.8 |
Brain cholinesterase (U/L) |
|
|
|
||
Week 4 |
10.23 |
9.74 |
8.72* |
4.58** |
2.12** |
Week 8 |
9.13 |
8.74 |
8.08 |
3.89** |
2.01** |
Week 13 |
9.40 |
9.62 |
8.92 |
3.99** |
2.18** |
*significantly different to controls (p<0.05); **p<0.01; ***p<0.001
Applicant's summary and conclusion
- Conclusions:
- A NOAEL of 20 ppm (equivalent to 1.32 and 1.56 mg/kg bw/d in males and females respectively) can be determined for this study based on the inhibition of cholinesterase activity at higher dietary concentrations.
- Executive summary:
The neurotoxicity of fenitrothion was investigated in a 90 -day rat study. Groups of 12 male and 12 female Sprague-Dawley rats (main study) and groups of 15 male and 15 female rats (cholinesterase assessment) received fenitrothion in the diet at concentrations of 0, 6, 20, 60 and 200 ppm. Dietary concentrations were calculated to be equal to mean intakes of 0, 0.40, 1.32, 3.99 and 13.8 mg/kg bw/d in males; 0, 0.46, 1.56, 4.85 and 17.6 mg/kg bw/d in females) for 13 weeks. All animals were observed twice a day for their toxic signs and mortality. Body weight was recorded weekly and days of behavioral testing. Food consumption was recorded weekly for all animals. Functional observational battery (FOB) and motor activity assessments were performed pre-test and during Weeks 4, 8 and 13. At termination, 6 rats/sex/group were randomly selected for perfusion and those in the control and high dose groups underwent a neuropathological evaluation. The remaining animals in each group (6/sex) had their brains removed and then were subjected to necropsy. The brain of each of non-perfused rats in the control and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP). Cholinesterase activities (erythrocyte, plasma, brain) were measured at 4, 8 and 13 weeks (5/sex). No animal died and none were sacrificed prior to scheduled termination. No treatment-related toxic signs were noted in male rats. Four females in the 200 ppm group showed tremors on one or two days during the second week of treatment. The 200 ppm group females also showed a higher incidence of muzzle staining and brown staining along the tail during the study compared to the control group. Both males and females in the 200 ppm group and females in the 60 ppm group had significantly reduced body weights compared to the control group on Day 7. The 200 ppm group's mean body weight remained significantly lower on Day 14 and 21 for males and from Days 7 to 42 for females. Food consumption for the 200 ppm group males and females were significantly lower than the control group from Days 0 to 7. Food consumption for the 200 ppm group females remained significantly reduced from Days 7 to 14 but then increased significantly from Days 28 to 56 and from 84 to 91. No significant differences considered to be related to treatment were seen for the qualitative components of the FOB. Significantly lower values for the 200 ppm group females in forelimb grip strength during the 4th week and in hindlimb grip strength during the 8th week occurred. These differences were considered not to be indicative of neurotoxicity taking lower body weights for the 200 ppm group females. Body temperature values as well as motor activity levels were not significantly different between control and fenitrothion-treated gropus. Reductions in blood and brain cholinesterase levels were noted for males in the 60 and 200 ppm groups and females in the 20, 60 and 200 ppm groups. No gross pathological findings or neuropathological changes (including brain measurements) seen were attributed to treatment with fenitrothion. No significant increases in glial fibrillary acidic protein were detected between the control and high dose groups for either male or females. A NOAEL of 20 ppm (equivalent to 1.32 and 1.56 mg/kg bw/d in males and females respectively) can be determined for this study based on the inhibition of cholinesterase activity at higher dietary concentrations.
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